Nosocomial infection is a persistent problem in healthcare today and in the intensive care units, accounting for over 200,000 deaths annually. Ventilator-associated pneumonia (VAP) develops as a complication in 8 ? 28% of patients receiving mechanical ventilation, represents approximately 50% of ICU acquired infections. Specifically Pseudomonas aeruginosa (P.a.) infections account for up to 20% of all cases of hospital acquired pneumonia with mortality rate of ~30%. More than 60% of sepsis patients in ICU show evidence of cardiac dysfunction and acute bacterial pneumonia stresses the heart and suppresses ventricular function. Also many bacterial virulent factors activate TLRs in cardiomycytes and suppress the myocyte contractile function. Although cardiac dysfunction caused by inflammation during infection is thought to be the key driver of mortality in ICU pneumonia patients, broad anti-inflammatories do not effectively prevent death. Thus, understanding the cellular components involved in the cardiac inflammation and their impact on myocyte and fibroblast function would assist in the prevention of cardiac dysfunction in pneumonia patients. We have discovered that the infiltration of activated myeloid cells into the hearts of P.a. infected mice induces cardiac inflammation and apoptosis that leads to phenotypic switch of cardiac resident macrophages and causes cardiac damage. Specifically, we identified that P.a. infection induces miR155 expression which targets many genes required for myocyte contractile function. We are the first to discover the link between cardiac macrophages (effector molecule miR155) and myocyte contractile dysfunction and fibroblast activation (fibrosis) during bacterial infection. Thus we hypothesize that the infiltration of activated myeloid cells shifts anti-fibrotic cardiac resident macrophage (MHC-IIlow) into pro-fibrotic macrophages (MCH-IIhigh) through cardiac inflammation and apoptosis, which results in myocyte contractile dysfunction and fibroblast activation. The miR155 functions as a global regulator of myeloid cell infiltration and thus prevents the cardiac macrophage phenotypic switch. The goals of this research program are to 1) Define the molecular mechanism of myocyte contractile dysfunction and fibroblast activation during P. aeruginosa infection. 2) Investigate the role of cardiac macrophages in activation of intrinsic signaling pathways that cause cardiac dysfunction during sepsis. 3) Determine whether localized inhibition of cardiac inflammation preserves the heart function in invasive bacterial infections. We will use human inducible pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), human cardiac fibroblast, and human monocyte derived macrophages to test our hypothesis in vitro. For in vivo studies we will use knockout mouse models to accomplish our goals. Overall, the mission of my laboratory is to identify the important regulatory pathways and effector molecules to create therapies for cardiac dysfunction in pneumonia patients. Our basic research discoveries will jump-start the development new approaches and drugs to treat cardiac dysfunction in sepsis.